Differential acetylation of histones and transcription factors plays an important regulatory role in developmental processes, proliferation and differentiation. Aberrant acetylation or deacetylation leads to such diverse disorders as leukemia, epithelial cancers, fragile X syndrome and Rubinstein-Taybi syndrome. The various groups of histone acetyltransferases (CBP/p300, GNAT, MYST, nuclear receptor coactivators and TAFII250) and histone deacetylases are surveyed with regard to their possible or known involvement in cancer progression and human developmental disorders. Current treatment strategies are discussed, which are still mostly limited to histone deacetylase inhibitors such as trichostatin A and butyrate.

We have previously reported that a set of oral squamous cell carcinoma lines express speci®cally elevated cdk6 activity. One of the cell lines, SCC4, contains a cdk6 ampli®cation and expresses functional p16 ink4a , the other cell lines express undetectable levels of p16 ink4a , despite a lack of coding-region mutations. Two of the cell lines, SCC15 and SCC40 have a hypermethylated p16 ink4A promoter and a third cell line, SCC9, has a mutation in the p16 ink4a promoter. Using the demethylation agent 5-aza-2'-deoxycytidine, we showed that the p16 ink4a protein was re-expressed after a 5-day treatment with this chemical. One cell line, SCC15 expressed high levels of p16 ink4a . In this line, cdk6 activity was decreased after 5-aza-2'deoxycytidine treatment, and the hypophosphorylated, growth suppressive form of the retinoblastoma tumor suppressor protein pRB was detected. Expression of p16 ink4a persisted, even after the drug was removed and the cells expressed senescence-associated b-galactosidase activity. Ectopic expression of p16 ink4a with a recombinant retrovirus in this cell line also induced a similar senescence-like phenotype. Hence, it was possible to restore a functional pRB pathway in an oral squamous cell carcinoma line by inducing re-expression of endogenous p16 ink4a in response to treatment with a demethylating agent.

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